Salivary gland function, repair, and regeneration are compromised after loss of parasympathetic innervation. However, the role ofthe nerves in repair/regeneration remains poorly understood. The objective ofthis study is to investigate the mechanisms of neuronal-epithelial communication between the submandibular gland (SMG) and the parasympathetic submandibular ganglion during embryonic development. The specific aims are to: 1) determine the mechanisms by which acetylcholine released from the neurons influences epithelial morphogenesis, and 2) determine the mechanisms by which the neurotrophic growth factor neurturin, which is secreted from the epithelium, influences neuronal function and epithelial morphogenesis. Goals include: elucidating the signaling pathways activated by the nerves that govern epithelial progenitor ceil self-renewal versus differentiation, investigating the influence of acetylcholine/musarinic/EGFR signaling on progenitor cell migration and polarization, and identifying the mechanisms by which neurturin promotes both epithelial and neuronal survival and regeneration after gamma radiation-induced injury. These goals will be achieved using well-defined ex vivo SMG and organotypic culture models in conjunction with genetic, biochemical, immunochemical, and fluorescence imaging techniques. These studies will facilitate our understanding of how salivary glands develop, repair, and regenerate, with the long-term aim of providing therapeutic approaches for re-establishing glandular structure and function after disease or injury.